Depression, with its related conditions, is one of the most common mental disorders in the United States. It is estimated that about five percent of the adult population experiences a depressive episode in their lifetime that requires antidepressive drug therapy.
A chemical in the human brain, called serotonin, has been linked with depression and with other psychiatric disorders such as eating disorders, alcoholism, pain, anxiety and obsessive-compulsive behavior. Serotonin is a neural transmitter, a chemical that is used to send messages from one brain cell to another. Neurotransmitters bind to special receptor proteins in the membrane of nerve cells, like a key in a lock, triggering a chemical reaction within the cell. It has been found that drugs that enhance transmission of serotonin in the brain are useful in treating major psychiatric disorders such as depression. These drugs act as serotonin-uptake inhibitors.
Upon appropriate stimulation, the serotonin neuron in the brain releases serotonin. Once released, the serotonin is free for a short period of time before it is either metabolized or picked up again by another receptor protein on a serotonin neuron (called "serotonin reuptake"). Either metabolism or reuptake reduces the amount of free serotonin available. If reuptake is reduced, there is more serotonin available for transmission. Certain anti-depressive drugs, such as Prozac, operate to inhibit serotonin reuptake by binding with the serotonin receptor protein, effectively blocking the binding of the protein with the serotonin. Although Prozac has been found to be an effective anti-depressant treatment, it has side effects which can be serious. Prozac is known to bind to the serotonin receptor protein, but the responses of patients can differ widely. Some patients experience greater binding than others. If a patient is not responding to Prozac treatment, there is currently no way to determine why that is the case. Frequently, the physician will simply administer greater doses of the drug, a practice which will not necessarily lead to better results and which can enhance undesirable side effects.
Other serotonin reuptake inhibitors are also known which tend to be better tolerated than tricyclic agents such as Prozac. The structures of several of these inhibitors, and their affinity constants for the serotonin reuptake system (5-HT) as well as for other neurotransmitter reuptake systems, norepinephrine (NE) and dopamine (DA), are presented below in Table 1.
TABLE 1 ______________________________________ Inhibition of Monoamine Uptake by Antidepressants in Rat Synaptosomes (Ki in nM) Compound DA NE 5-HT ______________________________________ ##STR2## 520 720 70 cis, 1S, 4S, n = 1 Sertraline ##STR3## 60 20 50 trans, 1R, 4S, n = 1 Tametraline ##STR4## trans cis 2000 860 90 34 0.58 0.03 n = 0 Indatraline ##STR5## 48 5 5000 Nomifensine ##STR6## 1590 289 25 Fluoxetine ##STR7## 365 670 3.8 Nisoxetine ##STR8## -- 350 1.1 Paroxetine ______________________________________
Although therapy with several of these drugs may not be accompanied by side effects as serious as those sometimes attributed to Prozac, there is still a need for a method to monitor the treatment of patients with the drugs as well as a method for studying the efficacy of such drugs.
New and powerful imaging methods which enable one to assess the living brain in vivo and thereby monitor the effectiveness of drugs and substances that affect brain chemistry have recently been developed. Methods such as positron emission tomography (PET) and single photon emission tomography (SPECT) involve the administration to a patient of radioactive tracer substances comprising a ligand that binds to presynaptic or postsynaptic neuroreceptors in the patient's brain. Emissions (primarily gamma rays which are emitted from the positrons or photons emitted from the radioactive tracer) are measured. These emissions are indicative of the number and degree of occupancy of blocking of the neuroreceptors. The number of neuroreceptors and the degree of occupancy or blocking is calculated utilizing a mathematical model, and compared with an intra-person or inter-person control, to determine the degree of drug response. Further treatment of the patient with drugs is based upon the comparisons made. By using these imaging methods to monitor the serotonin reuptake sites, improved treatment of patients with psychiatric disorders such as depression should be possible.